ABSTRACT=In our original grant (R01CA63562), we evaluated the impact of a smoking cessation treatment which incorporated motivational feedback about genetic susceptibility to lung cancer. We found strong positive effects of genetic feedback on perceived risk, perceived quitting benefits, and fear arousal. While smokers receiving genetic feedback made more quit attempts, they were no more likely to quit than were smokers receiving standard minimal contact cessation treatment. Observing that the vast majority of smokers were unable to quit, even in the face of perceived vulnerability and heightened motivation, we became interested in the genetic basis of nicotine dependence and smoking cessation. The strongest evidence (by our group and others) supports the role of the dopamine transporter gene (SLC6A3) which regulates reuptake of dopamine at the synapse. This is consistent with a large body of data suggesting that the reinforcing effects of nicotine are due to its impact on the neurotransmitter dopamine. Thus, in this competitive renewal, we propose to extend our research by evaluating the role of SLC6A3 in the response of smokers to pharmacological smoking cessation treatment (bupropion/Zyban). We have selected bupropion because: (a) initial data from randomized clinical trials provide strong support for its efficacy as a smoking cessation treatment, and (b) bupropion has inhibitory effects of dopamine transport (the protein product of the SLC6A3 gene). The specific aims of the proposed research are: (1) to evaluate the role of genetic factors in response to standard smoking cessation treatment; (2) to evaluate the role of genetic factors in response to bupropion treatment; and (3) to evaluate the psychobiological mechanisms by which genotype and bupropion influence smoking cessation. The study will be a double blind randomized placebo-controlled clinical trial of bupropion in 600 adult male and female smokers. The factorial design includes one treatment factor (bupropion plus standard treatment (with nicotine patch) vs. placebo plus standard treatment with patch) and one subject factor (SLC6A3 genotype, genetically predisposed vs. genetically protected). Bupropion or placebo will be delivered over a 10-week treatment period. All subjects will receive standard minimal contact cessation treatment, which includes two in-person sessions plus five brief structured phone-counseling sessions. A major innovation of this study is that we will use a behavioral economics computer paradigm to evaluate the reinforcing value of nicotine at pre-treatment and during bupropion therapy. Other mediating outcomes (mood, withdrawal) will be assessed at pre-treatment and at multiple points during treatment. The primary smoking cessation outcomes will be assessed at 1-, 6- and 12- months post-treatment. The proposed research will be the first to examine the role of specific genetic factors in response to pharmacological therapy for smoking cessation and to evaluate novel mediating mechanisms. The long-term objective is to provide information necessary to match smoking cessation treatments to individuals, based on their genetic predispositions.